tbuckley/cabot-search huggingface dataset:
Abstract 5058: Recurrence risk prediction based on automatic histopathologic analysis of breast cancer using whole slide images
Authors: Geongyu Lee, Chungyeul Kim, Tae-Yeong Kwak, Sun Woo Kim, Hyeyoon Chang
Journal: Cancer Research (2022)

Abstract The RS (Recurrence Score) is the results of a 21-gene test assessing the likelihood of breast cancer recurrence for hormone-positive, HER2-negative, and node-negative breast cancer patients. We conducted an experiment to find out whether there is a correlation between the RS value derived through genetic testing and specific morphological characteristics of breast cancer tissues with the expectation that these morphological features could predict RS values. Deep learning was utilized to assess the morphology of the hematoxylin-eosin (H&amp;E) stained whole slide images (WSIs) of breast cancer. In this study, we used 125 breast cancer cases associated with H&amp;E stained WSIs and RS scores which were divided into 3 risk groups based on the RS values: the low-risk group with 49 cases, the intermediate-risk group with 59 cases, and the high-risk group with 17 cases (low-risk for RS &amp;lt; 18, high-risk for RS &amp;gt; 31, and intermediate-risk for RS in between). On each WSI, an expert pathologist has annotated invasive breast tumor regions. We divided WSIs into 512x512 patches and trained a deep CNN model to classify the patches as benign (including DCIS), low-risk, intermediate-risk, or high-risk. In determining the risk group of each WSI, all patches from the WSI were classified by the model first, and then their majority class was assigned to the WSI. A nested cross validation was adopted to evaluate how well the model generalizes. The performance of the algorithm is shown in Table 1. According to the results, our model was able to distinguish between the low-risk group and the high-risk group to some extent. In particular, there was no case of misclassifying the low-risk group as high-risk. Since these high-risk patients require radiological examination, there is an advantage that the 21-gene test is not required. Although our model has yielded modest results, we believe that future studies through the integration of additional data with other clinical and pathological data will yield better results. Result Table 21-gene test result (*ground truth) Low Intermediate High Prediction Low 42 14 0 Intermediate 5 44 8 High 2 1 9 Accuracy 0.932 0.776 0.912 Sensitivity 0.857 0.746 0.529 Specificity 0.816 0.803 0.972 PPV 0.851 0.772 0.750 Citation Format: Geongyu Lee, Chungyeul Kim, Tae-Yeong Kwak, Sun Woo Kim, Hyeyoon Chang. Recurrence risk prediction based on automatic histopathologic analysis of breast cancer using whole slide images [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5058.
Abstract 5355: Mechanisms of resistance to CLN-081 (TAS6417) in non-small cell lung cancer with <i>EGFR</i> exon 20 insertions
Authors: Takuma Hayashida, Yosuke Kagawa, Shunta Mori, Liu jie, Yukie Kashima, Kosuke Tanaka, Hibiki Udagawa, Hiroki Izumi, Susumu Kobayashi
Journal: Cancer Research (2022)

Abstract Background: EGFR exon 20 insertions are detected in approximately 10% of EGFR mutant non-small cell lung cancer (NSCLC). NSCLC with EGFR exon 20 insertions is resistance to conventional epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as osimertinib. CLN-081 is a novel EGFR-TKI which shows promising anti-tumor activity for EGFR exon 20 insertions in an ongoing clinical trial. However, previous studies of other EGFR-TKIs prompted us to hypothesize that tumors would acquire resistance to CLN-081 over time. Investigation of the mechanisms of resistance to CLN-081 will provide novel therapeutic strategies for patients with CLN-081-resistant NSCLC. Methods: We first generated Ba/F3 cells stably expressing EGFR exon 20 insertions (Ba/F3-A767_S768insSVD and Ba/F3-Y764_V765insHH) and human patient-derived cells (PDCs), BID007 and BID019 harboring A763_Y764insFQEA and N771_P772insH, respectively. These cells were treated with increasing concentrations of CLN-081 to establish resistant cells. EGFR kinase domain was sequenced for parent Ba/F3 cell and resistant Ba/F3 clones to identify acquired EGFR mutations in resistant clones. PDC cells resistant to CLN-081 were subjected to whole exome sequencing (WES) and RNA sequencing (RNA-Seq) to examine whether resistant cells harbor acquired mutations and/or show changes in gene expression. Results: Sequencing of the EGFR kinase domain revealed the Cys797Ser (C797S) mutations in all resistant clones of Ba/F3-A767_S768insSVD and Ba/F3-Y764_V765insHH cells. WES of resistant PDC cells showed that both BID007 and BID019 cells acquired mutations in KMT2C, a gene involved in histone methylation. In addition, acquired mutations were found in several kinases such as DGKZ, PAK2, and ROCK1. RNA-Seq showed that several genes involved in inflammatory responses and antigen presentation were upregulated in PDC cells resistant to CLN-081. Conclusion: Our preclinical study identified several mechanisms of resistance to CLN-081 including acquired mutations and inflammatory responses. These results will provide new insights into development of a novel strategy to overcome or prevent resistance to CLN-081. Citation Format: Takuma Hayashida, Yosuke Kagawa, Shunta Mori, Liu jie, Yukie Kashima, Kosuke Tanaka, Hibiki Udagawa, Hiroki Izumi, Susumu Kobayashi. Mechanisms of resistance to CLN-081 (TAS6417) in non-small cell lung cancer with EGFR exon 20 insertions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5355.
Author Correction: B lymphocyte-derived acetylcholine limits steady-state and emergency hematopoiesis
Authors: Maximilian J. Schloss, Maarten Hulsmans, David Rohde, I-Hsiu Lee, Nicolas Severe, Brody H. Foy, Fadi E. Pulous, Shuang Zhang, Konstantinos D. Kokkaliaris, Vanessa Frodermann, Gabriel Courties, Chongbo Yang, Yoshiko Iwamoto, Anders Steen Knudsen, Cameron S. McAlpine, Masahiro Yamazoe, Stephen P. Schmidt, Gregory R. Wojtkiewicz, Gustavo Santos Masson, Karin Gustafsson, Diane Capen, Dennis Brown, John M. Higgins, David T. Scadden, Peter Libby, Filip K. Swirski, Kamila Naxerova, Matthias Nahrendorf
Journal: Nature Immunology (2022)
Abstract 5981: Single cell RNA sequencing uncovers high-plasticity cell state during tumor metastasis
Authors: Yu Zhang, Ching Ngar Wong, Lanqi Gong, Xin-yuan Guan, Beibei Ru, Beilei Liu
Journal: Cancer Research (2022)

Abstract Cancer metastasis remains the key barrier for patient’s cure. Tumor metastasis initiating from a single disseminated cell into the invasive nodule in the foreign microenvironment is poorly understand. In this study, we established the intravenous injection pulmonary metastatic model followed by single-cell RNA sequencing of disseminating cells from mice lungs at different timepoints, we identified a cluster of SLPI-high esophageal squamous cell carcinoma (ESCC) cells that mediates the lung metastasis evolution and predicts worse overall survival of ESCC patients. GSEA analysis reveals that the SLPI-high subset is functionally associated with epithelial-to-mesenchymal transition and neutrophil activation during lung metastasis. Immune infiltration prediction from TIMER also confirmed that high SLPI is tightly correlated with more abundance of neutrophils in the ESCC tumor microenvironment. SLPI is reported to drive the metastasis progression through regulating the vascular mimicry. In the next step, further in-vitro and in-vivo studies is required to explore the role of SLPI in ESCC cells in promoting lung metastasis evolution. We identified a SLPI+ ESCC cells with high pluripotency that particularly initiates the metastasis process. Citation Format: Yu Zhang, Ching Ngar Wong, Lanqi Gong, Xin-yuan Guan, Beibei Ru, Beilei Liu. Single cell RNA sequencing uncovers high-plasticity cell state during tumor metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5981.
Silver nanoclusters show advantages in macrophage tracing in vivo and modulation of anti-tumor immuno-microenvironment
Authors: Xu Yan, Yu Qi, Liting Ren, Juan Ma, Ming Xu, Tian Xia, Sijin Liu
Journal: Journal of Controlled Release (2022)

Macrophage-based nanomedicine represents an emerging powerful strategy for cancer therapy. Unfortunately, some obstacles and challenges limit the translational applications of macrophage-mediated nanodrug delivery system. For instance, tracking and effective cell delivery for targeted tumor sites remain to be overcome, and controlling the states of macrophages is still rather difficult due to their plastic nature in response to external stimuli. To address these critical issues, here, we reported a novel type of silver nanoclusters (AgNCs) with excellent fluorescent intensity, especially long-lasting cell labeling stability after endocytosis by macrophages, indicating promising applications in tracking macrophage-based nanomedicine delivery. Our mechanistic investigations uncovered that these merits originate from the escape of AgNCs from lysosomal degradation within macrophages. In addition, the AgNCs would prime the M1-like polarization of macrophages (at least in part) through the toll-like receptor 4 signaling pathway. The engineered macrophages laden with AgNCs could be employed for lung metastasis breast cancer treatment, showing the effective targeting propensity to metastatic tumors, remarkable regulation of tumor immune microenvironment and inhibition of tumor growth. Collectively, AgNC-trained macrophages appear to be a promising strategy for tumor immune-microenvironment regulation, which might be generalized to a wider spectrum of cancer therapeutics.
Abstract 3691: Dynamic BH3 profiling identifies novel combinations in malignant pleural mesothelioma with <i>in vivo</i> efficacy
Authors: Danielle S. Potter, Ruochen Du, Kin-Hoe Chow, Keith L. Ligon, Raphael Bueno, Anthony Letai
Journal: Cancer Research (2022)

Abstract Currently, malignant pleural mesothelioma (MPM) is mainly treated with conventional therapies such as surgery, chemotherapy and radiation, and patients often suffer from the lack of second line therapy options. In this study, we aimed to identify efficacious drug combinations in primary MPM patient samples and novel MPM patient-derived xenograft (PDX) models to provide better therapeutic options for MPM patients. BH3 profiling is a functional assay that measures mitochondrial priming of the cell. It uses BH3 peptides derived from the BH3 domain of pro-apoptotic BH3-only Bcl-2 family members to provoke a response from viable mitochondria. When tumor cells are treated with drugs prior to BH3 profiling, early changes in their apoptosis signaling can be captured before frank apoptosis occurs. This method is termed dynamic BH3 profiling (DBP), which has been applied in multiple cancer types to identify efficacious drugs. Here, we used high throughput dynamic BH3 profiling (HTDBP) to assess hundreds of drug treatments simultaneously to identify drug combinations that increased apoptotic priming in primary MPM cells ex vivo. Next, we created novel MPM PDX models and tested these drug combinations to determine the ones that primed MPM PDX cells. The HTDBP result from MPM PDX cells recapitulated the chemical vulnerabilities of the primary MPM cells. Moreover, one of the top combination candidates that comprised of navitoclax (BCL-xL, BCL-2 and BCL-w antagonist) and AZD8055 (mTORC1/2 inhibitor) was shown to be safe and efficacious in vivo in our CPDM_011x MPM PDX model. Finally, on the molecular level, we revealed that treatment with navitoclax drove the anti-apoptotic dependence of MPM cell lines towards MCL-1, whose level was downregulated by AZD8055 treatment. In this study, we identified a novel drug combination for MPM with HTDBP that consists of navitoclax and AZD8055. In addition, our results further corroborated that DBP, as a functional assay, can be used to rationally construct novel drug combinations to improve treatment outcomes for cancer patients. Citation Format: Danielle S. Potter, Ruochen Du, Kin-Hoe Chow, Keith L. Ligon, Raphael Bueno, Anthony Letai. Dynamic BH3 profiling identifies novel combinations in malignant pleural mesothelioma with in vivo efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3691.
Abstract 1014: A framework for research scientists to include patient advocates in cancer research
Authors: Hillary Stires, Igor Bado, Thelma Brown, Martha Carlson, Isaac S. Chan, Gloria V. Echeverria, Andrew J. Ewald, Carla Lloyd, Julia Maues, Steffi Oesterreich, Robert N. Riter, Kelly Shanahan, Alana L. Welm, Josh Newby
Journal: Cancer Research (2022)

Abstract The inclusion of patient advocates in basic cancer research has emerged as a valuable practice to ensure research is intentional, to support effective communication with broader audiences, and to directly connect researchers with those whom they are striving to help. Despite this value, many researchers do not work with patient advocates. To understand why and build a roadmap for more engagement in the future, we hosted a workshop with patient advocates and research scientists then presented findings and discussed further at an international conference. We acknowledged four main barriers: 1) It is not clear to everyone why patient advocates should be included in research, 2) Researchers are worried about saying the wrong thing, 3) Researchers do not know where to meet patient advocates, and 4) Researchers do not know how to include patient advocates in research. We identified best practices from various organizations and opportunities to overcome these barriers in the short- and long-term. This is the first time a multi-stakeholder group has come together to provide ways to support research scientists with overcoming barriers to regularly working with patient advocates. Ultimately, these relationships will improve cancer research and more quickly accomplish our collective goal of improving lives of those who have been diagnosed with cancer. Citation Format: Hillary Stires, Igor Bado, Thelma Brown, Martha Carlson, Isaac S. Chan, Gloria V. Echeverria, Andrew J. Ewald, Carla Lloyd, Julia Maues, Steffi Oesterreich, Robert N. Riter, Kelly Shanahan, Alana L. Welm, Josh Newby. A framework for research scientists to include patient advocates in cancer research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1014.
Abstract 2460: Assessing the effectiveness of transarterial chemoembolization using super-resolution ultrasound imaging and a rat model of hepatocellular carcinoma
Authors: Junjie Li, Katherine Brown, Megan Yociss, John Eisenbrey, Kenneth Hoyt
Journal: Cancer Research (2022)

Abstract Introduction: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide. Transarterial chemoembolization (TACE) treatment of HCC restricts the blood supply to the tumor. Conventional assessment of tumor response is performed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) or computed tomography (DCE-CT) at 4 to 6 weeks after the TACE procedure. An earlier indication of treatment effectiveness would improve patient management and prognosis. Super-resolution ultrasound (SR-US) imaging allows a ten-fold improvement in spatial resolution compared to traditional ultrasound (US) and allows visualization of microvascular networks. The goal of this preclinical research study was to use SR-US imaging to assess the effectiveness of TACE treatment in a relatively brief time frame. Methods: Eight male Sprague Dawley rats weighing around 300 g were injected with 5 million N1S1 cells in the upper left liver lobe and the tumors were allowed to grow for 14 days. The TACE procedure consisted of transhepatic arterial delivery of a mixture of 25 µL Lipiodol and 25 µL Doxorubicin (10 mg/kg) via a polyethylene microcatheter. After intravenous injection of a microbubble (MB) contrast agent, contrast-enhanced US images were acquired (N = 3000) with a preclinical system (Vevo 3100, FUJIFILM VisualSonics Inc) equipped with an MX201 linear array transducer. US images were processed to remove high motion frames, followed by tissue suppression filtering, and then MB localization and accumulation. Morphological filtering was used to enhance the vessel structures. In vivo US, MRI, and CT imaging were performed at baseline before TACE and again at 1 and 2 wk. After euthanasia, tumor tissue was removed for ex vivo analysis. Results: A rat model of HCC for assessing TACE treatment was introduced. Based on tumor size changes and residual perfusion after the TACE procedure, treatments were determined to be a complete responder, partial responder, or non-responder. Initial results demonstrate that SR-US imaging can sensitively detect any reduction in HCC perfusion as measured by a microvascular density (MVD) metric within 2 wk after a single TACE procedure. MVD measurements from the SR-US images were consistence with tumor volume data from MRI and CT imaging. Conclusions: In vivo SR-US images of tumor microvascular networks provided insight into treatment efficacy. Citation Format: Junjie Li, Katherine Brown, Megan Yociss, John Eisenbrey, Kenneth Hoyt. Assessing the effectiveness of transarterial chemoembolization using super-resolution ultrasound imaging and a rat model of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2460.
Abstract 5823: Studying the role of microRNAs that target stem cell genes in the emergence of tumor heterogeneity in development of human colorectal cancers
Authors: Victoria A. Stark, Caroline O. B. Facey, Lynn M. Opdenaker, Bruce M. Boman
Journal: Cancer Research (2022)

Abstract We investigated miRNAs that are implicated to target genes that encode different stem cell markers (SC) during tumorigenesis of colorectal cancer (CRC), one of the leading causes of cancer deaths in the US. One reason behind the lack of efficacy in cancer drug therapeutics is due to the development of tumor heterogeneity. We hypothesize that different miRNAs target different SC genes, which leads to the emergence of multiple cancer SC (CSC) subpopulations and tumor heterogeneity. Flow cytometry helped evaluate the expression of multiple SC markers including ALDH1, CD166, LGR5, and LRIG1 in the HT29 CRC cell line. CSC sub-populations were isolated using fluorescence activated cell sorting (FACS) and the expression of miRNAs in each CSC subpopulation was measured using NanoString profiling. The differential expression of miRNAs between CSC subpopulations helped rank the different levels of miRNA upregulation in each of the CSC subpopulations. The mRNAs predicted to be targeted by the most significantly upregulated miRNAs were identified using bioinformatics analysis via NanoString and mRNAs were classified according to their predicted function by David functional annotation analysis. Altogether, our results indicate that multiple CSC subpopulations exist in the HT29 cell-line, and we identified unique miRNA signatures for each CSC subpopulation. Moreover, the mRNAs predicted to be targeted by the miRNAs in each CSC subpopulation were found to have different functional classifications. We conclude that multiple CSC subpopulations emerge in HT29 cells due to the expression of unique miRNAs that target different SC genes (and their co-expressed genes), resulting in the emergence of multiple CSC subpopulations and tumor heterogeneity. Citation Format: Victoria A. Stark, Caroline O. B. Facey, Lynn M. Opdenaker, Bruce M. Boman. Studying the role of microRNAs that target stem cell genes in the emergence of tumor heterogeneity in development of human colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5823.
Abstract 3159: CUX1 dosage-dependent regulation of hematopoietic stem and progenitor cells
Authors: Weihan Liu, Stephanie Konecki, Tanner Martinez, Megan McNerney
Journal: Cancer Research (2022)

Abstract The mechanism by which stem and progenitor cells commit to proliferate, self-renew, or differentiate towards different lineages remains unclear. Understanding this process is essential to decipher both normal tissue development and aberrant differentiation associated with malignant transformation. CUX1 is a non-clustered HOX-family transcription factor that is recurrently mutated in hematopoietic and solid tumours and regulates cell fate in multiple developmental systems. We reported that CUX1 is required for normal hematopoietic homeostasis of both murine and human hematopoietic stem and progenitor cells (HSPCs). To date, the transcriptional role of CUX1 in HSPCs has been unclear, partly because of the complexity of the Cux1 locus. Namely, Cux1 shares exons with a distinct gene, Casp, which encodes a highly expressed golgi-associated protein. As most transcriptomic studies combine Casp and Cux1 transcripts, the nuances of Cux1 expression are concealed. To identify the transcriptional mechanism by which CUX1 regulates HSPC functions, we compared scRNA-seq data of Kit+lin- HSPCs from transgenic mice expressing inducible shRNAs targeting Cux1, Cux1mid and Cux1low, to control counterparts expressing an shRNA targeting renilla luciferase. We demonstrate that separating Cux1 from Casp transcripts provides more power to detect the influence of Cux1 in scRNA-seq data analysis. While cell numbers within most HSPC sub-populations are largely unchanged after five days of Cux1 knockdown, the transcriptomes within multiple clusters are disrupted. The effect size is greatest in Cux1low cells, compared to Cux1mid, consistent with dosage dependent roles of CUX1 in HSPCs. Across sub-populations, Cux1 levels correlated with gene signatures of “stemness,” and Cux1 knockdown disrupted this gene signature in the core hematopoietic stem cell (HSC) population. Concomitantly, low levels of Cux1 led to upregulation of cellular metabolism and G2/M cell cycle transition pathways in core HSCs, indicating that CUX1 regulates stem cell quiescence at the hematopoietic apex. We are currently integrating this data with epigenetic datasets to determine the mechanism by which CUX1 regulates critical hematopoietic transcriptional programs. Overall, understanding the regulatory function of CUX1 will provide insight into how HSCs commit to different fates and may ultimately lead to novel cancer therapeutic interventions. Citation Format: Weihan Liu, Stephanie Konecki, Tanner Martinez, Megan McNerney. CUX1 dosage-dependent regulation of hematopoietic stem and progenitor cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3159.